Globally, an estimated 35.3 million people were living with human immunodeficiency virus (HIV) in 2012, which is an increase from previous years as a result of the wider availability of life-saving antiretroviral therapies (ART). There were 2.3 million new HIV infections globally, representing a 33% decline in the number of new infections from 3.4 million in 2001. At the same time, the number of acquired immunodeficiency syndrome (AIDS) deaths is also declining with 1.6 million AIDS deaths in 2012, down from 2.3 million in 2005. From 1996 to 2012, ART averted 6.6 million AIDS-related deaths worldwide, including 5.5 million deaths in low- and middle-income countries (UNAIDS Report on the Global AIDS Epidemic 2013). In 2012, 9.7 million people in low- and middle-income countries received ART, representing 61% of all who were eligible under the 2010 World Health Organization (WHO) HIV treatment guidelines. However, under the 2013 WHO guidelines, the HIV treatment coverage in low- and middle-income countries represented only 34% of the 28.3 million people eligible in 2013.
Despite its proven success at saving lives, there are significant challenges to initiating and maintaining ART for all of those HIV-infected patients that need it in the world. ART must be taken life-long with near perfect adherence in order to be effective. This places extreme pressure and costs on international donors and over-taxed health systems in developing countries where HIV prevalence rates are highest. Moreover, ART has both short-term and long-term side effects for users, and drug resistance rates rise as more people are on treatment for longer periods of time. Thus, alternative or complementary treatments, including a therapeutic vaccine, which could induce a true or “functional” cure of HIV infection and lessen or eliminate the need for lifelong ART for HIV infected individuals, would therefore be of great benefit.
Studies of HIV vaccine in HIV-uninfected and infected subjects suggest that a successful HIV vaccine program will need to induce immunity against the diverse strains and subtypes that are predominant in the target populations. Improving magnitude, breadth and depth of epitope coverage is thought to be a key to developing a successful T-cell based preventive HIV vaccine. Published primate data indicate that the number of epitope specific responses induced by a vaccine may be an important immune correlate of viral load control in the simian immunodeficiency virus (SIV) challenge system (Chen et al. Nat Med. (2001) 7(11), 1225-31). Strategies to accomplish this include using multivalent vaccines containing immunogens from a number of prevalent subtypes or using mosaic sequences, proteins assembled from natural sequences by in silico recombination, which are optimized for potential T-cell epitopes.
The enhancement of host-mediated clearance of residual virus represents a new additional approach to an HIV functional cure (Carcelain et al. Immunol Rev. (2013) 254(1), 355-71). Findings of several studies have shown the importance of cellular immunity in the control of HIV reservoir size. HIV-1 Gag-specific CD8+ T cells isolated from elite controllers, but not from patients given ART, were shown to kill autologous resting CD4+ T cells in which the virus was reactivated with vorinostat. Moreover, functional anti-viral CD8 T cells are associated with reduced size of the central memory CD4 T cell reservoir in patients controlling their virus without ART. High-avidity multifunctional CD8 cytotoxic T lymphocytes (CTL) that target vulnerable regions in Gag are especially important in limiting virus diversity and reservoirs in individuals infected with HIV who have protective human leukocyte antigen (HLA) class I alleles. Therapeutic vaccines could re-stimulate CD8+ CTL to prevent or control virus relapses and re-establish latent infection in CD4+ T cells after treatment interruptions. A few therapeutic vaccine studies, such as the Ad5 HIV-1 gag vaccine (ACTG A5197 NCT00080106), and infusions of dendritic cells pulsed with inactivated HIV particles have shown transient viral suppression after treatment interruption. Eramune-02 is testing whether a deoxyribonucleic acid (DNA) prime, replication defective, recombinant adenovirus serotype-5 boost strategy, with the Vaccine Research Center's polyvalent HIV-Gag, Pol, Nef, and Env vaccine can reduce the viral reservoir in patients undergoing an ARV-intensification regimen (Katlama Lancet. (2013) 381(9883), 2109-17).
In contrast to patients who initiated ART in the course of chronic HIV infection, many patients who begin ART at the time of acute HIV infection demonstrate blunted or delayed rebound viremia after analytical treatment interruption (ATI) (Gianella et al. Antiviral therapy. (2011) 16(4), 535-45; Goujard et al. (2012) Antiviral therapy. 17(6), 1001-9; Hamlyn et al. (2012) PloS one. 7(8), e43754; Lodi et al. (2012) Archives of internal medicine. 172(16), 1252-5; Saez-Cirion et al. (2013) PLoS pathogens 9(3), e1003211). Several studies have shown sustained viremic control after treatment interruption in 5%-16% of patients initiated on ART at the time of acute infection (Gianella 2011, supra; Goujard 2012, supra; Grijsen 2012, supra; Lodi 2012, supra; Saez-Cirion 2013, supra). In these studies, factors associated with successful viremic control included shorter duration from HIV onset to ART initiation, longer duration on ART and low PBMC-associated HIV DNA (Williams et al. (2014) Elife 3, e03821).
However, ATI is not the standard of care for HIV infection. The Thai National HIV Treatment Guidelines, recently revised in 2014, now recommend lifelong ART for all persons living with HIV (PLHIV). However, the possibility of safely stopping or interrupting ART would hold great benefit both for patients, who are inconvenienced by having to take medications that require strict adherence and have a number of proven short-term and long-term toxicities, and by national health programs, which are committed to providing medications to hundreds of thousands or even millions of patients for decades to come.
Accordingly, there is a need in the art for improved methods of treating HIV-infected subjects, particularly HIV-infected subjects undergoing antiretroviral therapy (ART), such as therapeutic vaccines. Such a therapeutic vaccine preferably would improve immune responses to HIV and allow treated subjects to discontinue ART while maintaining viremic control.